This application titled P75NTR Small Molecule Ligands for Down Syndrome Therapy is in response to NINDS Exploratory/Developmental Projects in Translational Reseach (R21; program announcement: PAR-11-293). The current proposal will test whether small molecule ligands for the p75 neurotrophin receptor (p75NTR) will be effective treatments for neurodegeneration associated with Down syndrome (DS). An alteration most notably associated with DS is reduction of nerve growth factor, which binds to p75NTR expressed by basal forebrain cholinergic neurons (BFCN), the degeneration of which is a pathological hallmark of the disorder. The Longo laboratory previously found that p75NTR ligands, developed by the applicant and his colleague, prevent atrophy of BFCN and cognitive deficits in a mouse model of Alzheimer's disease (AD). To date, there is no known small molecule capable of restoring trophic support to BFCN, functioning at a specific target receptor, penetrating the blood brain barrier via oral administration, and lacking undesirable side-effects. Thus, these novel p75NTR ligands are now poised for efficacy testing in DS. In addition to deleterious effect on neurodevelopment, DS has neurodegenerative consequences that include pathology resembling AD and a significant prevalence of AD-type dementia in the fourth decade of life. The proposed studies will use a transgenic mouse model of DS to execute two aims: (i) determine if two (lead and backup) p75NTR ligands will slow the emergence of, or prevent, memory deficits associated with DS using a battery of behavioral tests; and (ii) test whether p75NTR ligands ameliorate classic DS-related cholinergic neuropathology. Positive results in these studies will identify a novel and feasible therapeutic strategy for reducing hallmark DS phenotypes, which are currently untreatable. The current R21 proposal is designed to provide proof-of-concept and target validation data that will support a subsequent U01 application to determine the effectiveness of these novel small molecule p75NTR ligands against DS.